Metformin

Metformin is a biguanide oral hypoglycaemic agent and the established first-line pharmacological treatment for type 2 diabetes mellitus worldwide.

It reduces hepatic glucose output, increases peripheral glucose uptake and utilisation (particularly in skeletal muscle), and decreases intestinal glucose absorption.

Unlike sulphonylureas, metformin does not stimulate insulin secretion and therefore does not cause hypoglycaemia when used as monotherapy.

The UK Prospective Diabetes Study (UKPDS) demonstrated that metformin reduces diabetes-related mortality and macrovascular complications, particularly in overweight patients.

NICE NG28 recommends metformin as the initial pharmacological therapy for type 2 diabetes in all adults, titrated to the maximum tolerated dose. Metformin typically reduces HbA1c by 1.0-1.

5 percentage points. A modest weight-neutral to weight-reducing effect distinguishes it from many other glucose-lowering agents.

It is also used off-label in polycystic ovary syndrome (PCOS) for insulin resistance. Metformin has an extensive safety record spanning over 60 years of clinical use.

Take metformin with or immediately after meals to reduce gastrointestinal side effects. Swallow tablets whole with water. Immediate-release tablets are usually taken two or three times daily.

Modified-release tablets are taken once daily with the evening meal. Do not crush modified-release tablets.

Dose escalation should be gradual (every 1-2 weeks) to minimise gastrointestinal intolerance. Maintain adequate fluid intake.

If you experience persistent vomiting or diarrhoea, temporarily withhold metformin and seek medical advice, as dehydration increases the risk of lactic acidosis.

Inform your doctor before any procedure requiring iodinated contrast media, as metformin should be withheld before and for 48 hours after contrast administration.

Immediate-release: Start at 500 mg once or twice daily with meals. Increase by 500 mg every 1-2 weeks. Usual maintenance dose: 500 mg three times daily or 1000 mg twice daily.

Maximum dose: 2000 mg daily (BNF) or 3000 mg daily (SmPC).

Modified-release: Start at 500 mg once daily with the evening meal. Increase by 500 mg every 1-2 weeks. Maximum dose: 2000 mg once daily.

In renal impairment: eGFR 30-44 mL/min/1.73m² — maximum 500 mg twice daily (or 1000 mg daily); eGFR <30 — contraindicated.

Review renal function before initiation and at least annually (more frequently in those approaching eGFR 45). Elderly patients require regular renal monitoring.

Side effects per SmPC frequency categories.

Very common (≥1/10): Gastrointestinal symptoms — nausea, vomiting, diarrhoea, abdominal pain, loss of appetite.

These affect up to 25% of patients, are usually dose-related, transient, and improve with continued use or dose reduction. Taking with food and slow titration significantly reduce incidence.

Modified-release formulations have better GI tolerability.

Common (≥1/100 to <1/10): Metallic taste, vitamin B12 deficiency (with long-term use, reported in 5-10% of patients).

Uncommon (≥1/1,000 to <1/100): Elevated liver enzymes, hepatitis (resolves on discontinuation).

Very rare (<1/10,000): Lactic acidosis — a potentially fatal metabolic emergency characterised by nausea, vomiting, abdominal pain, hyperventilation, hypothermia, and coma.

Incidence is approximately 3-10 per 100,000 patient-years and occurs predominantly in patients with contraindicated renal impairment, severe hepatic failure, or acute conditions causing tissue hypoxia.

Lactic acidosis is the most serious adverse effect of metformin, though extremely rare when prescribing guidelines are followed.

Risk factors include renal impairment, hepatic failure, excessive alcohol intake, dehydration, severe infection, and any condition causing tissue hypoxia (shock, acute heart failure, respiratory failure).

Patients should be educated about the symptoms of lactic acidosis and instructed to stop metformin and seek emergency care if they occur.

Withhold metformin for 48 hours before and after surgical procedures under general anaesthesia and before iodinated contrast media investigations.

Monitor vitamin B12 levels periodically during long-term treatment, particularly in patients with megaloblastic anaemia or peripheral neuropathy.

Metformin does not cause hypoglycaemia as monotherapy but may contribute when combined with sulphonylureas or insulin.

Metformin is contraindicated in patients with eGFR <30 mL/min/1.

73m², diabetic ketoacidosis, diabetic pre-coma, severe hepatic insufficiency, conditions causing tissue hypoxia (cardiac or respiratory failure, recent MI, shock), severe dehydration, alcohol intoxication, and hypersensitivity to metformin or any excipient.

Temporary discontinuation is required for iodinated contrast procedures and surgical interventions under general anaesthesia.